In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats

Research output: Contribution to journalJournal articlepeer-review

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In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats. / Saljic, Arnela; Soattin, Luca; Trachsel, Dagmar S.; Boddum, Kim; Jespersen, Thomas.

In: Journal of Molecular and Cellular Cardiology, Vol. 147, 10.2020, p. 18-26.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Saljic, A, Soattin, L, Trachsel, DS, Boddum, K & Jespersen, T 2020, 'In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats', Journal of Molecular and Cellular Cardiology, vol. 147, pp. 18-26. https://doi.org/10.1016/j.yjmcc.2020.07.011

APA

Saljic, A., Soattin, L., Trachsel, D. S., Boddum, K., & Jespersen, T. (2020). In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats. Journal of Molecular and Cellular Cardiology, 147, 18-26. https://doi.org/10.1016/j.yjmcc.2020.07.011

Vancouver

Saljic A, Soattin L, Trachsel DS, Boddum K, Jespersen T. In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats. Journal of Molecular and Cellular Cardiology. 2020 Oct;147:18-26. https://doi.org/10.1016/j.yjmcc.2020.07.011

Author

Saljic, Arnela ; Soattin, Luca ; Trachsel, Dagmar S. ; Boddum, Kim ; Jespersen, Thomas. / In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats. In: Journal of Molecular and Cellular Cardiology. 2020 ; Vol. 147. pp. 18-26.

Bibtex

@article{5e2c4d3f50714212a9d453cf490fad41,
title = "In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats",
abstract = "Introduction: GapmeRs are oligonucleotides that bind to a specific RNA sequence and thereby affecting posttranscriptional gene regulation. They therefore hold the potential to manipulate targets where current pharmacological modulators are inefficient or exhibit adverse side effects. Here, we show that a treatment with a GapmeR, mediating knockdown of small conductance Ca2+-activated K+ channels (SK3), has an in vivo protective effect against atrial fibrillation (AF) in rats.Material and methods: A unique SK3-GapmeR design was selected after thorough in vitro evaluation. 22 rats were randomly assigned to receive either 50 mg/kg SK3-GapmeR or vehicle subcutaneously once a week for two weeks. Langendorff experiments were performed seven days after the last injection, where action potential duration (APD(90)), effective refractory period (ERP) and AF propensity were investigated. SK3 channel activity was evaluated using the SK channel blocker, ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine). SK3 protein expression was assessed by Western Blot.Results: The designed GapmeR effectively down-regulate the SK3 protein expression in the heart (48% down-regulation, p = 0.0095) and did indeed protect against AF. Duration of AF episodes elicited by burst pacing in the rats treated with SK3-GapmeR was reduced 78% compared to controls (3.7 s vs. 16.8 s, p = 0.0353). The number of spontaneous AF episodes were decreased by 68% in the SK3-GapmeR group (39 episodes versus 123 in the control group, respectively) and were also significantly shorter in duration (7.2 s versus 29.7 s in the control group, p = 0.0327). Refractoriness was not altered at sinus rhythm, but ERP prolongation following ICA application was blunted in the SK3-GapmeR group.Conclusion: The selected GapmeR silenced the cardiac SK3 channels, thereby preventing AF in rats. Thus, GapmeR technology can be applied as an experimental tool of downregulation of cardiac proteins and could potentially offer a novel modality for treatment of cardiac diseases.",
keywords = "Atrial fibrillation, SK3 channels, Antisense oligonucleotides, GapmeR, CA2+-ACTIVATED K+ CHANNELS, POTASSIUM CHANNELS, RNA THERAPEUTICS, MESSENGER-RNA, ATHEROSCLEROSIS, CHOLESTEROL, INHIBITION, DELIVERY",
author = "Arnela Saljic and Luca Soattin and Trachsel, {Dagmar S.} and Kim Boddum and Thomas Jespersen",
year = "2020",
month = oct,
doi = "10.1016/j.yjmcc.2020.07.011",
language = "English",
volume = "147",
pages = "18--26",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats

AU - Saljic, Arnela

AU - Soattin, Luca

AU - Trachsel, Dagmar S.

AU - Boddum, Kim

AU - Jespersen, Thomas

PY - 2020/10

Y1 - 2020/10

N2 - Introduction: GapmeRs are oligonucleotides that bind to a specific RNA sequence and thereby affecting posttranscriptional gene regulation. They therefore hold the potential to manipulate targets where current pharmacological modulators are inefficient or exhibit adverse side effects. Here, we show that a treatment with a GapmeR, mediating knockdown of small conductance Ca2+-activated K+ channels (SK3), has an in vivo protective effect against atrial fibrillation (AF) in rats.Material and methods: A unique SK3-GapmeR design was selected after thorough in vitro evaluation. 22 rats were randomly assigned to receive either 50 mg/kg SK3-GapmeR or vehicle subcutaneously once a week for two weeks. Langendorff experiments were performed seven days after the last injection, where action potential duration (APD(90)), effective refractory period (ERP) and AF propensity were investigated. SK3 channel activity was evaluated using the SK channel blocker, ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine). SK3 protein expression was assessed by Western Blot.Results: The designed GapmeR effectively down-regulate the SK3 protein expression in the heart (48% down-regulation, p = 0.0095) and did indeed protect against AF. Duration of AF episodes elicited by burst pacing in the rats treated with SK3-GapmeR was reduced 78% compared to controls (3.7 s vs. 16.8 s, p = 0.0353). The number of spontaneous AF episodes were decreased by 68% in the SK3-GapmeR group (39 episodes versus 123 in the control group, respectively) and were also significantly shorter in duration (7.2 s versus 29.7 s in the control group, p = 0.0327). Refractoriness was not altered at sinus rhythm, but ERP prolongation following ICA application was blunted in the SK3-GapmeR group.Conclusion: The selected GapmeR silenced the cardiac SK3 channels, thereby preventing AF in rats. Thus, GapmeR technology can be applied as an experimental tool of downregulation of cardiac proteins and could potentially offer a novel modality for treatment of cardiac diseases.

AB - Introduction: GapmeRs are oligonucleotides that bind to a specific RNA sequence and thereby affecting posttranscriptional gene regulation. They therefore hold the potential to manipulate targets where current pharmacological modulators are inefficient or exhibit adverse side effects. Here, we show that a treatment with a GapmeR, mediating knockdown of small conductance Ca2+-activated K+ channels (SK3), has an in vivo protective effect against atrial fibrillation (AF) in rats.Material and methods: A unique SK3-GapmeR design was selected after thorough in vitro evaluation. 22 rats were randomly assigned to receive either 50 mg/kg SK3-GapmeR or vehicle subcutaneously once a week for two weeks. Langendorff experiments were performed seven days after the last injection, where action potential duration (APD(90)), effective refractory period (ERP) and AF propensity were investigated. SK3 channel activity was evaluated using the SK channel blocker, ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine). SK3 protein expression was assessed by Western Blot.Results: The designed GapmeR effectively down-regulate the SK3 protein expression in the heart (48% down-regulation, p = 0.0095) and did indeed protect against AF. Duration of AF episodes elicited by burst pacing in the rats treated with SK3-GapmeR was reduced 78% compared to controls (3.7 s vs. 16.8 s, p = 0.0353). The number of spontaneous AF episodes were decreased by 68% in the SK3-GapmeR group (39 episodes versus 123 in the control group, respectively) and were also significantly shorter in duration (7.2 s versus 29.7 s in the control group, p = 0.0327). Refractoriness was not altered at sinus rhythm, but ERP prolongation following ICA application was blunted in the SK3-GapmeR group.Conclusion: The selected GapmeR silenced the cardiac SK3 channels, thereby preventing AF in rats. Thus, GapmeR technology can be applied as an experimental tool of downregulation of cardiac proteins and could potentially offer a novel modality for treatment of cardiac diseases.

KW - Atrial fibrillation

KW - SK3 channels

KW - Antisense oligonucleotides

KW - GapmeR

KW - CA2+-ACTIVATED K+ CHANNELS

KW - POTASSIUM CHANNELS

KW - RNA THERAPEUTICS

KW - MESSENGER-RNA

KW - ATHEROSCLEROSIS

KW - CHOLESTEROL

KW - INHIBITION

KW - DELIVERY

U2 - 10.1016/j.yjmcc.2020.07.011

DO - 10.1016/j.yjmcc.2020.07.011

M3 - Journal article

C2 - 32768409

VL - 147

SP - 18

EP - 26

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -

ID: 251634252